III.A. Natural history and determinants of survival in patients with ZES. Little is known about athe natural history or determinants of long term survival in patients with malignant pancreatic endocrine tumor syndromes. In collaboration with Dr. David Venzon, NCI, these parameters were analyzed in 185 patients with ZES. Tumor size, location, presence or absence of MEN-1 were all found to be factors in determining metastatic rate tot he liver which was the primary determinant of survival. Two clinical forms of ZES a benign and malignant form were identified. This study for the first time identifies clinical parameters that can be used to determine the natural history and used to develop specific treatments. III.B. Possible benefit of surgical resection in gastrinoma patients. Controversy exists whether patients with ZES should undergo surgical exploration. In collaboration with the Surgical Metabolism Section, NCI, the longterm courses of patients with ZES who did and did not undergo surgical exploration for possible cure were analyzed. A significantly lower (p less then 0.0003) rate of development of hepatic metastases in resected patients support the need for surgery in gastrinoma patients and other PET's. III.C. Prospective study of surgical resection of gastrinomas in MEN-1. The surgical treatment of patients with ZES and MEN-1 is controversial. A recent study proposes the gastrinoma is frequently duodenal in location and is curable. With Dr. D. Fraker, NCI, 10 such patients were studied. Not all gastrinomas were duodenal in location (70%). Furthermore, no patients were curable either because of multiple tumors or lymph node metastases. This study shows that ZES cannot be cured in patients with MEN-1 with simple gastrinoma enucleation or resection. III.D. Intrahepatic arterial stimulation (IAS) with secretin in localizing metastatic gastrinomas. Identification of liver metastases is essential in the management of patients with pancreatic endocrine tumors (PET'), however, it may be difficult. We have recently developed methods for finding primary tumors measuring hormone gradients after provocative agents. With Dr. John Doppman, Diagnostic Radiology Department, we prospectively studied this method for identifying hepatic metastases in patients with ZES. Using established criteria, IAS was helpful in 22% of the 74 patients studied. This methodology with other provocative agents may be useful in PET's in resolving hepatic involvement.